Once there was a day when all type C nonmyelinated neurons were indistinguishable. That time of histologic analysis has passed, and we have entered an era of unparalleled technological insight into the mechanisms of pain and pruritus. Since the description of the capsaicin receptor, transient receptor protein vanilloid 1 (TRPV1), in 1997, we have seen the number of related sensor ion channels, G protein-coupled receptors, and signaling proteins explode. Specific nociceptive pathways have been identified based on their sensitivity to mechanical, heat, chemical, and cold stimuli. Pruritus is now recognized to have both histamine-sensitive and histamine-independent afferent arcs. Cross-talk between C-fibre systems and myelinated neural pathways has become more complex, but through complexity, a new reality of sensory coding is emerging. A multitude of novel therapeutics have been and are in planning and production stages. These will almost certainly revolutionize our understanding and treatment of pain and itch by the end of this decade.